A PREMIXED ROOM TEMPERATURE STABLE COMPOSITION OF FAMOTIDINE FOR INTRAVENOUS BOLUS INJECTION AND METHOD THEREOF

Description

EARLIEST PRIORITY DATE

This Application claims priority from a complete patent application filed in India having patent application Ser. No. 20/224,1054109, filed on Sep. 21, 2022, and titled “A PREMIXED ROOM TEMPERATURE STABLE COMPOSITION OF FAMOTIDINE FOR INTRAVENOUS BOLUS INJECTION AND METHOD THEREOF.” and a PCT Application no. PCT/IB2023/055159 filed on May 19, 2023, and titled “A PREMIXED ROOM TEMPERATURE STABLE COMPOSITION OF FAMOTIDINE FOR INTRAVENOUS BOLUS INJECTION AND METHOD THEREOF.”

FIELD OF INVENTION

Embodiments of the present disclosure relate to the field of medicinal preparations, and more particularly to a premixed room temperature stable composition of famotidine for intravenous bolus injection and method thereof.

BACKGROUND

Famotidine is a medicine used to treat patients whose stomach produces excess acid or have ulcers. The famotidine has an ability to inhibit gastric acid secretion through a histamine H2-receptor. The histamine H2-receptor includes blocking agents capable of inhibiting secretion of gastric acid induced by gastrin histamine, methacholine or food. Method of administration of the famotidine may include intravenous bolus and intravenous infusion. The famotidine is a basic compound having an acid dissociation constant (pKa) of about 7.1 and shows potential of hydrogen (pH) dependent solubility and stability characteristics.

The famotidine exhibits a low stability at an acidic pH while the solubility extremely decreases at a neutral pH range where the stability is high. The famotidine undergoes extensive hydrolytic degradation to form mainly famotidine sulfamoyl propenamide, famotidine propenamide and famotidine propionic acid. The famotidine is also susceptible to oxidative degradation to form mainly famotidine disulfide and famotidine sulfoxide. As per the pharmaceutical standards, an acceptance criterion of not more than 5.0% for the sum of the peak areas for famotidine sulfamoyl propanamide, famotidine propenamide and famotidine propionic acid is being followed. Further it is desired to limit the level of oxidative impurities such as famotidine disulfide and famotidine sulfoxide to not more than 1.0%, preferably not more than 0.5% during shelf life.

Currently, famotidine injections available in the market includes a sterile concentrated solution with a concentration of 10 milligrams per milliliter. The sterile concentrated solution has a potential of hydrogen (pH) value of 5.3 to achieve the desired aqueous solubility. The sterile concentrated solution is unstable and therefore needs to be stored under refrigerated conditions to achieve longer shelf life. Refrigeration and storage of the sterile concentrated solution requires special handling. Further, due to hypotonic and sterile concentrated solution nature, of the sterile concentrated solution, the famotidine requires aseptic dilution with a compatible intravenous solution before administration. The sterile concentrated solution may be administered over a period of at least two minutes as intravenous bolus injection.

The famotidine injections available in the market also include a sterile solution with a concentration of 20 milligrams per 50 milliliter. Such a premixed solution is intended for administration as an intravenous infusion over a duration ranging between 15 minutes and 30 minutes, however the solution is unsuitable for intravenous bolus injection due to high volume required to be administered. Currently, the medical field lacks the famotidine injections that are suitable for intravenous bolus administration readily without any dilution, which can be stored at room temperature.

Further, the need for prior dilution of the famotidine injections may have several associated problems. The associated problems may include contamination of the famotidine injections, product wastage, possibility of dosage miscalculation, and a greater chance of needle sticks to medical personnel. The prior dilution may also produce medical wastes in the form of vials, needles and bags.

Hence, there is a need for an improved premixed room temperature stable composition of famotidine for intravenous bolus injection and method thereof to address the aforementioned issue(s).

BRIEF DESCRIPTION

In accordance with an embodiment of the present disclosure, a premixed room temperature stable composition of famotidine for intravenous bolus injection is provided. The composition includes 0.20 to 0.50 percentage by weight famotidine. The composition also includes a buffering agent. The composition further includes one or more tonicity adjusting agents. The composition includes potential of hydrogen value between 5.7 and 6.4. In accordance with another embodiment of the present disclosure, a method for preparing a premixed room temperature stable composition of famotidine for intravenous bolus injection is provided. The method includes mixing famotidine and a buffering agent to obtain a first solution. The famotidine includes a concentration ranging between 2 milligrams per millilitres to 5 milligrams per millilitres. The method also includes dissolving one or more tonicity adjusting agents to the first solution to obtain a second solution. The second solution includes osmolality ranging between 260 milliosmoles and 330 milliosmoles. The method further includes adjusting potential of hydrogen value of the second solution in between 5.7 and 6.4 by one or more pH adjusting agents thereby preparing the ready to use famotidine injection.

To further clarify the advantages and features of the present disclosure, a more particular description of the disclosure will follow by reference to specific embodiments thereof, which are illustrated in the appended figures. It is to be appreciated that these figures depict only typical embodiments of the disclosure and are therefore not to be considered limiting in scope. The disclosure will be described and explained with additional specificity and detail with the appended figures.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure will be described and explained with additional specificity and detail with the accompanying figures in which:

FIG. 1 is a block diagram representation of a premixed room temperature stable composition of famotidine for intravenous bolus injection in accordance with an embodiment of the present disclosure; and

FIG. 2 is a flow chart representing the steps involved in a method of preparation of premixed room temperature stable composition of famotidine for intravenous bolus injection in accordance with an embodiment of the present disclosure.

Further, those skilled in the art will appreciate that elements in the figures are illustrated for simplicity and may not have necessarily been drawn to scale. Furthermore, in terms of the construction of the device, one or more components of the device may have been represented in the figures by conventional symbols, and the figures may show only those specific details that are pertinent to understanding the embodiments of the present disclosure so as not to obscure the figures with details that will be readily apparent to those skilled in the art having the benefit of the description herein.

DETAILED DESCRIPTION

For the purpose of promoting an understanding of the principles of the disclosure, reference will now be made to the embodiment illustrated in the figures and specific language will be used to describe them. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended. Such alterations and further modifications in the illustrated system, and such further applications of the principles of the disclosure as would normally occur to those skilled in the art are to be construed as being within the scope of the present disclosure.

The terms “comprises”, “comprising”, or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such a process or method. Similarly, one or more devices or sub-systems or elements or structures or components preceded by “comprises . . . a” does not, without more constraints, preclude the existence of other devices, sub-systems, elements, structures, components, additional devices, additional sub-systems, additional elements, additional structures, or additional components. Appearances of the phrase “in an embodiment”, “in another embodiment” and similar language throughout this specification may, but not necessarily do, all refer to the same embodiment.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The system, methods, and examples provided herein are only illustrative and not intended to be limiting.

In the following specification and the claims, reference will be made to a number of terms, which shall be defined to have the following meanings. The singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.

Embodiments of the present disclosure relate to a premixed room temperature stable composition of famotidine for intravenous bolus injection and method thereof. The composition includes 0.20 to 0.50 percentage by weight famotidine. The composition also includes a buffering agent. The composition further includes one or more tonicity adjusting agents. The composition includes potential of hydrogen value between 5.7 and 6.4.

FIG. 1 is a block diagram representation of a premixed room temperature stable composition 10 of famotidine 30 for intravenous bolus injection 20 and method thereof in accordance with an embodiment of the present disclosure. The composition 10 includes 0.20 to 0.50 percentage by weight famotidine 30. The composition 10 also includes a buffering agent 40. The composition 10 further includes one or more tonicity adjusting agents 50. The composition 10 includes potential of hydrogen value between 5.7 and 6.4. In one embodiment, the famotidine 30 may include concentration between 2 milligrams per milliliters and 5 milligrams per milliliters. In such an embodiment, preferable concentration of the famotidine 30 may be 4 milligrams per milliliters.

Further, in one embodiment, the buffering agent 40 may include L-aspartic acid adapted to resist change in potential of hydrogen (pH) value of the composition 10. In one embodiment, the buffering agent 40 may include 0.08 to 0.20 percentage by weight. In one embodiment, the one or more tonicity adjusting agents 50 may include at least one of mannitol, sodium chloride and dextrose to adjust tonicity of the composition 10.

Furthermore, in some embodiment, the composition 10 may include sodium hydroxide to adjust potential of hydrogen (pH) value of the composition 10. In such an embodiment, the sodium hydroxide solution used for the pH adjustment preferably may have a normality of 0.1. In a specific embodiment, the composition 10 may include an antioxidant adapted to minimize formation of oxidative impurities including at least one of famotidine disulphide.

Also, in one embodiment, the antioxidant may include thiol group containing antioxidant chosen from monothioglycerol, L-Cysteine, and the like. In such an embodiment, the monothioglycerol may have percentage by weight between 0.025 to 0.1 with respect to the composition 10. In some embodiments, the composition 10 may include a preservative to prevent microbial contamination of the composition 10. In such an embodiment, the preservative may include at least one of benzyl alcohol, and parabens.

Composition 10 having famotidine concentration of 20 milligrams per 5 millilitres (20 mg/5ml) is shown in table 1.

TABLE 1
Composition 10 having famotidine concentration
of 20 milligrams per 5 millilitres (20 mg/5 ml)

			Formula 1:
			20 mg/5 ml (4 mg/ml)
Sr.			Premixed product

No	Ingredient	Function	mg/mL	% w/v
1	Famotidine 30 USP	Active substance	4.0	0.40
2	L-aspartic acid, USP	Buffering agent 40	1.6	0.16
3	Mannitol, USP	Tonicity adjusting	8.0	0.80
4	Sodium chloride, USP	agents 50	7.0	0.70

5	Sodium hydroxide, NF	pH adjusting agent	q.s. to adjust pH
			to about 5.8-6.2

6	Water for Injection,	Vehicle	q.s. to	q.s. to
	USP		1 mL	100.00%

7	Nitrogen, NF	Processing aid

The processing aid, nitrogen may be used to reduce dissolved oxygen levels in the composition 10, and to reduce oxygen content in vial headspace and also for aiding filtration process by pressurization of bulk solution. Stability of the composition 10 having famotidine concentration of 4 milligrams per milliliters at different pH ranging pH 5.8 to pH 6.4 in accelerated (40° Celcius (C)/75% Relative Humidity (RH)) and long-term stability (25° C./60% RH) conditions at inverted orientation of the vial is provided in Table 2, Table 3 and Table 4.

Stability data of the composition 10 having famotidine concentration of 4 milligrams per millilitres at a pH of about 5.8 is shown in Table 2.

TABLE 2
Stability data of the composition 10 having famotidine concentration
of 4 milligrams per millilitres at a pH of 5.8

	Accelerated stability condition	Long term stability condition
	40° C./75% RH	25° C./60% RH

Test	Initial	1 Month	2 Month	3 Month	1 Month	2 Month	3 Month
Description	Clear	Clear	Clear	Clear	Clear	Clear	Clear
	Colourless	Colourless	Colourless	Colourless	Colourless	Colourless	Colourless
	solution	solution	solution	solution	solution	solution	solution
pH	5.89	6.22	6.09	6.08	6.05	5.99	5.98
Osmolality	282	291	289	286	290	288	288
(mosmoles/kg)
Assay	97.7	100.1	98.4	96.3	100.8	101.5	100.0
(% w/v)

Related substances (% w/w)

Sulfoxide	0.01	0.01	BDL	0.03	0.02	0.01	0.01
Impurity
Famotidine	BDL	0.02	0.06	0.19	BDL	BDL	0.02
Amidine
Propanamide	BDL	0.2	0.63	1.16	0.02	0.03	0.05
impurity
USP Impurity-D
Sulfamoyl	0.08	0.81	1.47	1.60	0.25	0.36	0.47
propenamide
USP Impurity-C
Propionic acid	0.04	0.02	BDL	BDL	BDL	BDL	BDL
impurity
USP Impurity-F
Impurity-G	0.08	0.06	0.06	0.03	0.06	0.07	0.04
Famotidine	0.06	0.17	0.22	0.41	0.10	0.08	0.11
disulphide
USP Impurity-E
Impurity at RRT	BDL	0.03	0.12	0.24	BDL	0.02	0.12
about 0.85
Impurity at RRT	0.02	0.06	0.08	0.11	0.03	0.03	0.06
2.30
Any unspecified	0.10	0.03	0.05	BDL	BDL	0.07	BDL
impurity
Total Impurities	0.31	1.34	2.79	4.08	0.47	0.57	0.86

Stability data of the composition 10 having famotidine concentration of 4 milligrams per milliliters at a pH of about 6.2 is shown in Table 3.

TABLE 3
Stability data of the composition 10 having famotidine concentration
of 4 milligrams per milliliters at a pH of 6.2

	Accelerated stability condition	Long term stability condition
	40° C./75% RH	25° C./60% RH

Test	Initial	1 Month	2 Month	3 Month	1 Month	2 Month	3 Month
Description	Clear	Clear	Clear	Clear	Clear	Clear	Clear
	Colourless	Colourless	Colourless	Colourless	Colourless	Colourless	Colourless
	solution	solution	solution	solution	solution	solution	solution
pH	6.21	6.35	6.42	6.36	6.29	6.34	6.37
Osmolality	286	293	294	291	293	289	291
(mosmoles/kg)
Assay (% w/v)	98.7	99.6	99.2	96.7	100.8	101.0	100.2

Related substances (% w/w)

Sulfoxide	0.01	0.03	BDL	0.03	0.01	BDL	0.02
Impurity
Famotidine	BDL	0.03	0.08	0.23	BDL	BDL	0.02
Amidine
Propanamide	BDL	0.10	0.31	0.54	0.01	0.04	0.05
impurity
USP Impurity-D
Sulfamoyl	0.06	0.54	1.05	1.21	0.18	0.29	0.36
propenamide
USP Impurity-C
Propionic acid	0.03	0.04	BDL	BDL	BDL	BDL	BDL
impurity
USP Impurity-F
Impurity-G	0.08	0.05	0.06	0.03	0.05	0.07	0.04
USP Impurity-E	0.06	0.42	0.38	0.70	0.11	0.15	0.17
Famotidine
disulfide
Impurity at RRT	BDL	0.03	0.12	0.24	BDL	0.02	0.12
about 0.85
Impurity at RRT	0.02	0.08	0.13	0.16	0.04	0.04	0.09
2.30
Any unspecified	0.10	0.03	0.05	BDL	BDL	0.07	BDL
impurity
Total Impurities	0.30	1.48	2.39	3.46	0.39	0.65	0.91

Stability data of the composition 10 having famotidine concentration of 4 milligram per milliliter at a pH of 6.4 is shown in table 4.

TABLE 4
Stability data of the composition 10 having famotidine concentration
of 4 milligram per milli liter at a pH of 6.4

	Accelerated stability condition	Long term stability condition
	40° C./75% RH	25° C./60% RH

Test	Initial	1 Month	2 Month	3 Month	1 Month	2 Month	3 Month
Description	Clear	Clear	Clear	Clear	Clear	Clear	Clear
	Colourless	Colourless	Colourless	Colourless	Colourless	Colourless	Colourless
	solution	solution	solution	solution	solution	solution	solution
PH	6.38	6.40	6.53	6.41	6.41	6.47	6.44
Osmolality	279	290	285	289	287	285	286
(mosmoles/kg)
Assay (% w/v)	97.4	98.1	97.3	94.8	97.5	93.9	97.1

Related substances (% w/w)

Sulfoxide	0.01	0.01	BDL	0.04	0.01	0.02	0.03
Impurity
Famotidine	BDL	0.03	0.08	0.24	BDL	BDL	0.03
Amidine
Propanamide	BDL	0.09	0.25	0.49	0.02	0.04	0.04
impurity
USP Impurity-D
Sulfamoyl	0.05	0.48	0.92	1.13	0.15	0.24	0.31
propenamide
USP Impurity-C
Propionic acid	0.04	0.04	BDL	BDL	BDL	BDL	BDL
impurity
USP Impurity-F
Impurity-G	0.07	0.05	0.06	0.03	0.05	0.06	0.04
USP Impurity-E	0.06	0.24	0.44	0.94	0.11	0.17	0.24
Famotidine
disulphide
Impurity at RRT	BDL	0.03	0.11	0.23	BDL	0.03	0.11
about 0.85
Impurity at RRT	0.02	0.09	0.14	0.15	0.04	0.05	0.10
2.30
Any unspecified	0.10	0.03	0.05	BDL	BDL	0.07	BDL
impurity
Total Impurities	0.28	0.95	2.29	3.71	0.36	0.72	0.99

Based on the table 2, table 3 and table 4, it may be observed that the famotidine 30 remained in the composition 10 throughout the assessed stability period between the pH 5.8 to pH 6.4 without any precipitation. Though levels of hydrolytic impurities such as sulfamoyl propenamide and propanamide were observed slightly higher at pH 5.8 compared to pH 6.2 and pH 6.4, the levels were within acceptable limits. The level of famotidine disulphide was observed at a higher level in pH 6.4 compared to pH of 6.2 and 5.8.

Composition 10 having famotidine concentration of 4 milligram per millilitre with an antioxidant, monothioglycerol at a concentration of 0.1 and 1 milligram per milliliter is shown in table 5.

TABLE 5
Composition 10 having famotidine concentration of 4 milligram per millilitre with
monothioglycerol having concentration of 0.1 or 1 milligram per milliliter

	Formula 2:	Formula 3:
	Premixed product	Premixed product
	with	with
	0.05 mg/mL	1 mg/mL
	antioxidant	antioxidant

Sr. No.	Ingredient	Function	mg/mL	% w/v	mg/mL	% w/v

1	Famotidine 30 USP	Active	4.0	0.40	4.0	0.40
		substance
2	L-aspartic acid,	Buffering agent	1.6	0.16	1.6	0.16
	USP	40
3	Mannitol, USP	Tonicity	8.0	0.80	8.0	0.80
	Sodium chloride,	adjusting	7.0	0.70	7.0	0.70
4	USP	agents 50
5	Monothioglycerol,	Antioxidant	0.05	0.005	1.0	0.1
	NF

6	Sodium hydroxide,	pH adjusting	q.s. to adjust pH to	q.s. to adjust pH to
	NF	agent	about 6.2	about 6.2
			(Range 5.7 to 6.4)	(Range 5.7 to 6.4)

7	Water for	Vehicle	q.s.	q.s.	q.s.	q.s.
	Injection, USP		to 1 mL	to 100.0%	to 1 mL	to 100.0%

8	Nitrogen, NF	Processing aid	Processing aid	Processing aid

Stability data of the composition 10 having famotidine concentration of 4 milli grams per millilitre along with monothioglycerol concentration of 1 milligrams per millilitre is shown in table 6.

TABLE 6
Stability data of the composition 10 having famotidine concentration of 4 milligram
per milliliter with monothioglycerol at 1 milligram per milliliter.

40° C./75% RH

25° C./60% RH

Test	Initial	Week 2	1 Month	2 Month	1 Month	2 Month
Description	Clear	Clear	Clear	Clear	Clear	Clear
	Colourless	Colourless	Colourless	Colourless	Colourless	Colourless
	solution	solution	solution	solution	solution	solution
pH	6.26	6.26	6.22	6.32	6.23	6.26
Osmolality	299	297	295	299	297	304
(mOsm/kg)
Assay (% w/v)	100.9	99.7	98.3	94.8	99.8	99.0

Related substances (% w/w)

Sulfoxide	BDL	BDL	0.08	0.09	0.18	0.12
Impurity
Famotidine	BDL	BDL	0.02	BDL	0.03	BDL
Amidine
Propanamide	0.01	0.08	0.20	0.38	0.04	0.05
impurity
USP Impurity-D
Sulfamoyl	0.09	0.33	0.72	1.00	0.24	0.30
propanamide
USP Impurity-C
Propionic acid	0.03	BDL	BDL	0.09	BDL	0.03
impurity
USP Impurity-F
USP Impurity-G	BDL	0.06	0.06	0.03	0.08	0.04
Famotidine	0.03	BDL	BDL	BDL	BDL	BDL
disulphide
USP Impurity-E
Impurity at RRT	0.021	0.04	0.07	0.12	0.02	0.04
about 0.85
Impurity at RRT	0.08	0.25	0.06	0.33	0.10	0.13
about 1.80
Impurity at RRT	0.07	0.08	0.14	0.39	0.08	0.11
about 2.30
Any unspecified	ND	0.07	0.11	0.12	0.06	0.07
impurity
Total impurities	0.29	0.94	1.5	2.50	0.9	0.83

From the table 6, it has been observed that inclusion of the monothioglycerol, minimised the presence of oxidative degradant, famotidine disulphide in the composition 10. Even though the impurity levels at RRT about 1.80 and RRT about 2.30 is found increasing in accelerated stability condition, the impurity levels at room temperature are found to be satisfactory.

In an exemplary embodiment, multi-dose vial composition 10 of multi-dose vial having a preservative and famotidine concentration of 4 milligrams per millilitres is shown in table 7.

TABLE 7
Composition 10 of multidose vial having a preservative and
famotidine concentration of 4 milligrams per millilitres

			Formula 4:
			Premixed, multidose
			vial having a
Sr.			preservative

No.	Ingredient	Function	mg/mL	% w/v
1	Famotidine (30) USP	Active substance	4.0	0.4
2	L-aspartic acid, USP	Buffering agent 40	1.6	0.16
3	Mannitol, USP	Tonicity adjusting	8.0	0.8
4	Sodium chloride, USP	agents 50	7.0	0.7
5	Benzyl alcohol NF	Preservative	3.6 to	0.36% to
			9.0	0.90%

6	Sodium hydroxide, NF	pH adjusting	q.s. to adjust pH
		agent	to about 6.2
			(Range 5.7 to 6.4)

7	Water for Injection,	Vehicle	q.s. to	q.s. to
	USP		1 mL	100.00%

8	Nitrogen, NF	Processing aid	Processing aid

Stability data of the composition 10 of 10 mL fill multi-dose vials of Formula 3 having famotidine concentration of 4 mg/mL and benzyl alcohol at 9 mg/mL is shown in table 8.

TABLE 8
Stability data of the composition 10 of multi-dose vials having
famotidine concentration of 4 mg/mL and 9 mg/mL benzyl alcohol

40° C./75% RH

25° C./60% RH

Test	Initial	1 Month	3 Month	1 Month	3 Month
Description	Clear	Clear	Clear	Clear	Clear
	Colourless	Colourless	Colourless	Colourless	Colourless
	solution	solution	solution	solution	solution
pH	6.18	6.17	6.20	6.16	6.19
Osmolality (mOsm/kg)	274	274	282	274	283
Assay (% w/v)	99.7	97.8	95.0	98.6	98.8
Benzyl Alcohol	99.2	98.2	98.1	98.0	99.5
(% label claim)
Benzaldehyde Content	0.01	0.07	0.02	0.03	0.01

Related substances (% w/w)

Sulfoxide Impurity	0.05	0.09	0.18	0.06	0.07
Famotidine Amidine	BDL	0.02	0.07	BDL	BDL
Propanamide impurity	BDL	0.12	0.65	0.02	0.05
USP Impurity-D
Sulfamoyl propanamide	0.07	0.53	1.25	0.19	0.38
USP Impurity-C
Propionic acid impurity	0.03	0.02	BDL	0.01	BDL
USP Impurity-F
USP Impurity-G	0.08	0.06	0.04	0.04	0.04
Famotidine disulphide	0.03	0.26	0.71	0.04	0.21
USP Impurity-E
Impurity at RRT about	0.09	0.04	0.25	0.01	0.13
0.85
Impurity at RRT about	BDL	0.07	0.17	0.04	BDL
1.80
Impurity at RRT about	0.01	0.04	0.09	0.02	BDL
2.30
Any unspecified impurity	ND	ND	0.12	ND	0.06
Total impurities	0.34	1.15	4.18	0.32	1.08

Composition 10 having famotidine concentration of 2 milligrams per millilitres and 5 milligrams per millilitres is shown in table 9.

TABLE 9
Composition 10 having famotidine concentration of 2 milligrams per millilitres
and famotidine concentration of 5 milligrams per millilitres.

	Formula 5:	Formula 6:
	Premixed product	Premixed product
	having	having
	2 mg/mL	5 mg/mL
	Famotidine	Famotidine

Sr. No.	Ingredient	Function	mg/mL	% w/v	mg/mL	% w/v

1	Famotidine 30	Active	2.0	0.2	5.0	0.5
	USP	substance
2	L-aspartic acid,	Buffering	0.8	0.08	2.0	0.2
	USP	agent 40
3	Mannitol, USP	Tonicity	4.0	0.4	50.0	5.0

Sodium chloride,

adjusting

8.0

0.8

Not used

4

USP

agents 50

5	Sodium	pH adjusting	q.s. to adjust pH to	q.s. to adjust pH to
	hydroxide, NF	agent	about 6.2	about 6.2
			(Range 5.7 to 6.4)	(Range 5.7 to 6.4)

6	Water for	Vehicle	q.s.	q.s.	q.s.	q.s.
	Injection, USP		to 1 mL	to 100.0%	to 1 mL	to 100.0%

7	Nitrogen, NF	Processing aid	Processing aid

Stability data of the composition 10 having famotidine concentration of 2 milligrams per millilitres is shown in table 10.

TABLE 10
Stability data of the composition 10 having famotidine
concentration of 2 milligrams per millilitres

40° C./75% RH

25° C./60% RH

Parameters	Initial	1 Month	3 Month	1 Month	3 Month
Description	Clear	Clear	Clear	Clear	Clear
	colourless	colourless	colourless	colourless	colourless
	solution, free	solution, free	solution, free	solution, free	solution, free
	from visible	from visible	from visible	from visible	from visible
	particles	particles	particles	particles	particles
pH	6.00	6.05	6.21	6.05	6.10
Osmolality	243	248	251	244	246
(mOsm/kg)

Related substances (% w/w)

Famotidine Amidine	BDL	BDL	BDL	BDL	BDL
USP Impurity-D	BDL	0.08	0.53	BDL	BDL
Propanamide
impurity
USP Impurity-C	0.04	0.62	1.67	0.16	0.38
Sulfamoyl
Propanamide
USP Impurity-F	BDL	BDL	0.22	BDL	BDL
Propionic acid
impurity
Total Impurities	0.04	1.11	2.65	0.22	0.38

Stability data of the composition 10 having famotidine concentration of 5 milligrams per millilitres is shown in table 11.

TABLE 11
Stability data of the composition 10 having famotidine
concentration of 5 milligrams per millilitres

Product pH 6.0

Stability test

25° C./60% RH

parameters	Initial	1 Month	2 Month	6 Month
Description	Clear	Clear	Clear	Clear
	colourless	colourless	colourless	colourless
	solution,	solution,	solution,	solution,
	free from	free from	free from	free from
	visible	visible	visible	visible
	particles	particles	particles	particles
pH	6.00	6.04	6.05	6.09

Related substances (% w/w)

Famotidine Amidine	BDL	BDL	BDL	BDL
USP Impurity-D	BDL	BDL	BDL	0.08
Propanamide impurity
USP Impurity-C	0.05	0.18	0.27	0.76
Sulfamoyl propanamide
USP Impurity-F	BDL	BDL	BDL	0.08
Propionic acid impurity
Highest unspecified	BDL	BDL	BDL	0.11
Impurity				(RRT-
				0.825)
Total Impurities	0.05	0.18	0.27	1.1

FIG. 2 is a flow chart representing the steps involved in a method 100 of preparation of a premixed room temperature stable composition of famotidine for intravenous bolus injection in accordance with an embodiment of the present disclosure. The method 100 includes mixing famotidine and a buffering agent to obtain a first solution in step 110. The famotidine includes a concentration ranging between 2 milligrams per milliliters to 5 milligrams per milliliters. The method 100 also includes dissolving one or more tonicity adjusting agents to the first solution to obtain a second solution in step 120. The second solution includes osmolality ranging between 260 milliosmoles and 330 milliosmoles. The method 100 further includes adjusting potential of hydrogen value of the second solution in between 5.7 and 6.4 by adding one or more pH adjusting agents, thereby preparing the ready to use famotidine injection 130.

Further, in one embodiment, the second solution may be made into batch volume. Aseptic filling of the second solution made into the batch volume may be done after filtering by sterilizing grade filters. In one embodiment, the one or more pH adjusting agents may include at least one of a sodium hydroxide solution and an aspartic acid solution. In such an embodiment, the sodium hydroxide solution may be having a normality of 0.1 N and the aspartic acid solution may be having a concentration of 0.5%. In one embodiment, the second solution may be cooled down to a temperature ranging between 20 degree celsius and 30 degree celsius after adjusting the potential of hydrogen value.

Exemplary steps involved in preparation of the ready to use famotidine injection having concentration of 20 milligrams per 5 milli liters is given below. Collect water for injection equivalent to 110% of the batch size and sparge with nitrogen gas to reduce the dissolved oxygen level to <1 ppm. Collect water for injection from the previous step equivalent to 60% of the batch size and heat to approximately 60° C.-70° C. Add and dissolve L-Aspartic acid, USP by mixing for Approx. 20 minutes. Cool the solution temperature to 20° C.-30° C. Maintain Nitrogen gas sparging of the solution throughout the process except during material addition. Add and dissolve Famotidine by mixing for Approx. 40 minutes to obtain a clear solution. Add and dissolve the tonicity adjusting agent, Mannitol and/or sodium chloride one after other by mixing for approx. 10 minutes after each ingredient addition. Adjust the pH to about 6.2 using 0.1N sodium hydroxide solution and/or 0.5% Aspartic acid solution and then make up the volume to batch volume. Filter the solution using suitable 0.2 micron sterilizing grade filters and fill 5 mL of the filtered solution in 5 mL, 13 mm neck, USP type 1 Glass vial. Blanket the vial headspace using Nitrogen gas to minimize the headspace oxygen level, preferably to less than 10%. Stopper the vials using 13 mm butyl rubber stopper.

Various embodiments of the composition of a premixed room temperature stable composition of famotidine for intravenous bolus injection and method thereof described above enable various advantages. The composition is suitable for intravenous bolus administration without any prior dilution. The composition is capable of being stored in room temperature, thereby eliminating the need of refrigeration. Also, the composition is suitable for intravenous bolus administration. Eliminating the need of prior dilution negates the chances of contamination of the composition during the dilution, product wastage, dosage miscalculations, needle sticks to the medical personnel and production of medical wastes in the form of vials, needles and bags. Further, room temperature stable injection gives an opportunity to store and transport the ready to use famotidine injection more efficiently.

It will be understood by those skilled in the art that the foregoing general description and the following detailed description are exemplary and explanatory of the disclosure and are not intended to be restrictive thereof. While specific language has been used to describe the disclosure, any limitations arising on account of the same are not intended.

The figures and the foregoing description give examples of embodiments. Those skilled in the art will appreciate that one or more of the described elements may well be combined into a single functional element. Alternatively, certain elements may be split into multiple functional elements. Elements from one embodiment may be added to another embodiment. For example, the order of processes described herein may be changed and are not limited to the manner described herein. Moreover, the actions of any flow diagram need not be implemented in the order shown; nor do all the acts need to be necessarily performed. Also, those acts that are not dependent on other acts may be performed in parallel with the other acts. The scope of embodiments is by no means limited by these specific examples.